Table 4.

Animal epilepsy models and the role of Arc protein.

Animal epilepsy models	Epilepsy symptoms and manifestations	Possible role of Arc in the control of epileptogenic activity	References
Non-genetic models
Mice' neuronal hippocampal and cortical cultures. Epileptogen's (4-Aminopyridine, bicuculline, forskolin) local administration	Synchronized network bursting in hippocampal cultures	Activity-induced Arc expression in neurons and astrocytes.	(106)
Temporal lobe epilepsy model (rats) pilocarpine-induced epilepsy	Status epilepticus	Optogenetics seizure control targeting intense ARC immunoreactive neurons Intense ARC immunoreactive neurons may have the potential to control epileptic seizures.	(112)
The mesial temporal lobe epilepsy model with the sclerotic hippocampus (mice) Optogenetically stimulated and kainic acid-induced epileptogenesis	Epileptiform events and status epilepticus in the hippocampus	The upregulation of Arc mRNA (1) is positively correlated with the epileptiform bursts, (2) increases during the increase of burst amplitudes and (3) increases with prolonged paroxysmal episodes. Arc is a possible mediator between synaptic plasticity and seizure activity.	(80)
Epilepsy after electroconvulsive shock treatment (rat) rat hippocampus and perirhinal cortex relationship between the current intensities that elicit seizures and the threshold for Arc mRNA transcription in the rat hippocampus and perirhinal cortex	Behavioral seizures with hind-limb extension and tonic–clonic motor responses	1. Intensive electrostimulation: the high proportion of Arc-positive neurons in the dentate gyrus, intermediate in the CA3 region of the hippocampus, lowest in the perirhinal cortex 2. Low-intensity electrostimulation: an opposite Arc expression profile (lowest in the dentate gyrus and highest in the perirhinal cortex)	(23)
Pentylenetetrazole-induced kindling in rats	The seizure intensity was classified according to the Racine scale	The most prominent increase in Arc expression during kindling was present in the entorhinal cortex, the dentate gyrus, and the basolateral nucleus of the amygdala	(107)
Intraperitoneal injection of pilocarpine to induce status epilepticus in rats	The seizure intensity was classified according to the Racine scale	Using Arc immunoreactivity as an indicator of granule cell activation, authors found that granule cells born after pilocarpine-induced SE did not express Arc more intensely than the surrounding granule cells and, in addition, transient seizure activity induced by pentylenetetrazol did not activate mature granule cells born after SE more intensely.	(110)
Electroconvulsive seizures in rats	Observation of generalized tonic/clonic seizure that lasted ~15 sec	Electroconvulsive seizures strongly induce prolonged Arc/Arg3.1 transcription in dentate granule cells. Assessment of Arc/Arg3.1 mRNA revealed that the induction of Arc/Arg3.1 transcription was blocked by NMDA receptor antagonists	(108)
Kainic acid-induced seizures in mice	Behavioral observation of the onset of seizure	Seizures elevated Arc/Arg3.1 protein in the granular cell layer and molecular layer of the dentate gyrus and in the pyramidal cells in CA1-3. The induction of a large number of activity-regulated genes, including Arc/Arg3.1, Arl5b, Gadd45b, Inhba, and Zwint, is indeed dependent on ERK phosphorylation.	(113)
Genetic models
Angelman syndrome mouse model (mice). AS mice lack a functional copy of maternally inherited UBE3A but with a wild-type copy of the paternally inherited UBE3A allele.	Enhanced seizure-like response to an audiogenic stimulus	The reduction of the level of Arc expression has the potential to reverse the seizures associated with Angelman syndrome	(68)
Angelman syndrome UBE3Am−/p+ model in mice	Field potential recording in brain slices	Local circuits of UBE3Am−/p+ in vitro are hyperexcitable and display a unique epileptiform activity	(114)
Transgenic mice that express EGFP-Arc	A single generalized electroconvulsive tonic/clonic seizure that lasted approximately 15 s.	Arc mRNA degradation occurs via a mechanism with characteristics of nonsense-mediated mRNA decay (NMD). Rapid dendritic delivery of newly synthesized Arc mRNA after induction may depend in part on prior splicing of the 3′UTR.	(115)
EGFP-tagged Arc in the primary culture of hippocampal neurons	Switch from tetrodotoxin-induced inactivity to BDNF treatment	Activity-induced Arc/Arg3.1 accumulates at spines during synaptic inactivity. Synaptic Arc/Arg3.1 reduces surface AMPAR levels in individual spines.	(29)
Patients with idiopathic generalized epilepsy including childhood absence epilepsy and juvenile myoclonic epilepsy	Absence epilepsy	Authors suggest the presence of an idiopathic generalized epilepsy susceptibility allele in the ARC gene.	(116)
Mutant mice with the deletion of the Drd1a gene to prevent dopamine D1 receptor expression	Behavioral and EEG observation of seizures	Administration of D1-type receptor agonists promotes the expression of Arc/Arg3.1 in the hippocampal dentate gyrus. Deletion of Drd1a gene prevents the effect	(105)
Wistar Albino Glaxo from Rijswijk (Wag/Rij) rats	Absence epilepsy	Hippocampal mGlu5 receptor-dependent synaptic plasticity is associated with the pathological phenotype of WAG/Rij rats. Arc is involved in mGluR-induced long-term synaptic depression (mGluR-LTD)	(117–119)
Arc–/– and Arc+/–mice	Electrical stimulation of dopamine neurons in the midbrain ventral tegmental area and Ca-imaging	Genetic disruption of Arc leads to concomitant hypoactive mesocortical and hyperactive mesostriatal dopamine pathways.	(120)
Arc−/− Mice Have Decreased Spine Density and Increased Spine Width. Kainite model	Arc−/− mice are more susceptible to seizures in response to systemic challenges with pentylenetetrazol (PTZ).	Arc specifically reduces surface GluR1 internalization at thin spines, and Arc mutants that fail to facilitate AMPAR endocytosis do not increase the proportion of thin spines. Loss of Arc in vivo leads to a significant decrease in the proportion of thin spines and an epileptic-like network hyperexcitability.	(21)